- Title
- OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis
- Creator
- Wroblewski, David; Jiang, Chen Chen; Croft, Amanda; Farrelly, Margaret L.; Zhang, Xu Dong; Hersey, Peter
- Relation
- PLoS One Vol. 8, Issue 12
- Publisher Link
- http://dx.doi.org/10.1371/journal.pone.0084073
- Publisher
- Public Library of Science
- Resource Type
- journal article
- Date
- 2013
- Description
- Anti-apoptotic Bcl-2 family proteins, in particular, Mcl-1, are known to play a critical role in resistance of human melanoma cells to induction of apoptosis by endoplasmic reticulum stress and other agents. The present study examined whether the BH3 mimetics, Obatoclax and ABT-737, which inhibit multiple anti-apoptotic Bcl-2 family proteins, would overcome resistance to apoptosis. We report that both agents induced a strong unfolded protein response (UPR) and that RNAi knockdown of UPR signalling proteins ATF6, IRE1a and XBP-1 inhibited Mcl-1 upregulation and increased sensitivity to the agents. These results demonstrate that inhibition of anti-apoptotic Bcl-2 proteins by Obatoclax and ABT-737 appears to elicit a protective feedback response in melanoma cells, by upregulation of Mcl-1 via induction of the UPR. We also report that Obatoclax, but not ABT-737, strongly induces autophagy, which appears to play a role in determining melanoma sensitivity to the agents.
- Subject
- melanoma; cancer; apoptosis; cell death; cell biology
- Identifier
- http://hdl.handle.net/1959.13/1044692
- Identifier
- uon:14361
- Identifier
- ISSN:1932-6203
- Language
- eng
- Full Text
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